The insulin-like growth factor binding protein-1 (IGFBP-1) is uniquely characterized among the family of IGF binding proteins by the characteristics that (1) circulating IGFBP-1 levels inversely correlate with fetal birthweights in multiple paradigms in both humans and rodents and (2) IGFBP-1 is tightly regulated by insulin and dramatically elevated under conditions of hypoinsulinemia such as occurs in insulin-dependent diabetes mellitus (IDDM). The exact in vivo functions of IGFBP-1 are unknown, however, considerable evidence supports the hypothesis that the family of six IGFBPs are major modulators of IGF-I and IGF-II, mitogenic peptides that mediate growth and metabolism. The proposed project will test the hypothesis that IGFBP-1 is a major regulator of IGF availability and has a critical role in fetal and postnatal growth and in glucose counterregulation. This hypothesis leads to the following testable predictions that: (1) IGFBP-1 will be present in embryonic circulation by mid-gestational ages, as early as IGFs are known to act in fetal growth. (2) IGFBP-1 deficiency during development will result in increased fetal and neonatal growth. (3) IGFBP-1 will attenuate growth and metabolic effects of chronic and acute IGF-1 challenge. (4) Chemical induction of IDDM in IGFBP-1 deficient mice will result in attenuation of secondary complications of diabetes that are the result of decreased IGF availability. (5) Either deficiency or overexpression of IGFBP-1 will alter the rate and amount of kidney hypertrophy associated with both uninephrectomy and chemically-induced IDDM. The proposed research will directly test these predictions using, in part, a powerful approach to establish a genetic mouse model that is deficient in IGFBP-1. These studies will provide a better understanding of the in vivo role of IGFBP- 1 in growth and metabolism during normal states and in specific pathological conditions.